3-(methylthio) chromone and s-oxide derivatives

ABSTRACT

The S-oxides are prepared by oxidation of II or by ring closure of o-hydroxy-omega substituted acetophenone with triethylorthoformate using base catalysts. The above compounds are useful in treating gastric hyperacidity.   WHEREIN X is O, O2 or non-existant. These compounds where X is non-existent are prepared as follows:   3-(Methylthio)chromone and S-oxide derivatives having the following structural formula are disclosed:

United States Patent Von Strandtmann et al.

[151 3,699,129 [4 1 Oct. 17, 1972 I I 221 Filed:

[73] Assignee: Warner-Lambert Company, Morris Plains, NJ.

July 15, 1971 [2]] Appl. No.: 165,757

521 u.s. Cl. ..260/345.2, 424/283 [5| I Int. Cl; ..C07d 7/34 [58] Field of Search ..'...260/345.2

.[56] References Cited OTHER PUBLICATIONS Becker et al., J.'Am.- Chem. soc. v01. 85, pp. 3410 Primary Examiner-John M. Ford AttorneyAlbert H. Graddis et al. I

ing the following structural formula aredisclosed:

wherein X is O, 0 or non-existant.

These compounds where X is non-existent are prepared as follows:

The S-oxides are prepared by oxidation of ll 'or by ring closure of o-hydroxy-omega substituted ac'etophenone with triethylorthofor'mate using base catalysts.

The above compounds are useful in treating gastric hyperacidity.

. 52mm QPHYKKQ W 3-(METHYLTHIO)CHROMONE AND S-OXIDE DERIVATIVES The present invention relates to new and novel 3- (Methylthio )chromon'e and S-oxide derivatives having the following structural formula: v

. if X s orn upon the se veri'ty, .age, sex and the species of the mammal being treated by methods well known to the healing arts. 1

ln' order to use these compounds, they are formulated into dosage forms such as tablets, with diluents such as lactose, mannitol and the like. Theyare also formulated into dosage forms suitable for intramuscu-' lar or subcutaneous injections by combining with diluents suchas peanut oil, water for injection and the like. These formulations are prepared by methods well known to the pharmacists art.

According to the present invention, when X is nonexistent, the compounds are prepared in accordance with the following scheme:

(see Method A below) or by ring closure of o-hydroxyomega-substituted acetophenone V or V1 with triethylorthoformate using base catalysts (see Method B below). These reactions schemes are as follows:

Starting compounds. l and EVI arezprepared: in -accordance with ouncependingapplication .-3,-(Methylsulfinyl) and '3-(Methylsulfonyl)-4-Chromanone Derivatives filed May 26, 197l,'Ser. No. 147,184. Starting compound V is prepared by the procedure of Becker et. al. J. Amer. Chem. Soc., 85, 3410 (1963).

In order to further illustrate the practice of this invention, the following examples are included: (Room temperature used hereinafter is between 20. to C).

EXAMPLE 1 3-(methylthio)chromone A quantity of 13.0 g (0.0619 mole) of 3-(methylsulfi v nyl)-4-chromanone was added portionwise to a stirred, cooled quantity of 150 ml of thionyl chloride over a- .period of five minutes, keeping the temperature at 20 C. After complete addition, the excess thionyl chloride The S-oxides are or V was distilled off at reduced pressure. Ice water (300 ml) was added tothe residue to destroy the excess thionyl chloride. Concentrated potassium hydroxide (about 10 M) was added to the oily mixture until strongly alkaline. The mixture was heated (without stirring) for about 10 minutes at about C on the steam bath. The mixture wascooled and the resulting semisolid was filtered and washed well with water. The damp crude was dissolved in 100 ml of methylene chloride and this solution was dried over K CO charcoaled, filtered and concentrated to about 10 ml volume when 100 ml of ether was added. The resulting o o I SCH: I

Cm 8001: C1 KOH so. 4 -t I o 0 crystals were filtered and washed with some ether; wt. 5.1 g (42.8 percent) m.p. 103 -l05 C.,Recrystallization from ethyl acetate gave pure material melting at 104-106 C. Anal. Calcd for c n o s; C, 62.48; H, 4.19; S,

16.68. Found: C, 62.64; H, 4.1 1; S, 16.45.

EXAMPLE 2 METHOD A 3-(methylsulfinyhchromone A solution of 3.79 g (0.0187 mole) of percent Inether an'd'ext'racted withSO ml of I l% potassium car bonate' solution. They organic phase was dried over lQCO charcoalcd, filtered and concentratedto give 2.5 "g (64.3 .percentlnear white crystals melting at l 49-l5 l C. Recrystallization from ethyl acetate gave pure white crystals melting at l 50'-l 52C.

Anal. Calcdfor C l-l O S: C, 57.69; H, 3.87; S, i540.Found:C;-57.84;H,'3L88;S,15.31.

M'ETHODB 0 (T) 3 CE:

Ii-(methylsulfinyl) chromone I I A mixture of 39.6 g (0.2 mole) of 2'-hydrox'y-2- (methylsulfinyl) ac etophe'none, I 150 ml of triethylorthoformate and [7.0 g (0.2 mole) of piperidine was heated with stirring to l l-l 20 C. The resulting redsolution was heated to 125 for minutes allowing volatiles to boil off. The crystals that separated 'on cooling were filtered, washed with triethylorthoformateand then with ether. Wt. 4.2 g

(10.1 percent). Recrystallization from ethyl acetate METHOD 5' 3-( methylsulfonyl )chromone A mixture of 6.6 g (0.031 mole) of 2'-h yd'roxy- 2- (m'ethylsulfonyl) I ace'tophenone, 50 ml 'of triethylorthoformate and 2 ml of piperidine was heated with stirring to l25-l35 C- for "minutes, allowing gave pure material, mp. l50-l52, identical to the I product isolated in Method A.

EXAMPLE 3 I METHOD A I B-r-CHE .3-(methylsulfonyl)chromone A solution .of 0.5 g (0.0024 mole) of 3-(methylsulfinyl)chromone and 0.489 g (0.0024 mole) of 85 percent m-chloroper'benzoicacid in 50 ml of chloroform was maintained at reflux for 15 minutes. The cooled reaction'mixture was extracted with 5 percent sodium bicarbonate, dried and concentrated to give 0.5 g (93.4%) of crude product. Recrystallization from chloroform ether gave pure crystals, mp. l72-l 73 C.

the volatiles to distill off. On cooling the dark solution yielded 4.7 g (67.8 percent) of tan crystals melting at l69--l7l C. Recrystallization from chloroform-ether gave pure white crystals melting at l72-l 73 C.

Anal. Calcd for'C l-l' o sz C, 53.56; H, 3.60; S, I 14.30. Found: C',53..7,l; l-l, 3.66; S, 14.58.

We claim: I l. A compound of the formula:

with thionyl chloride and basifying the. reaction mixture to obtain the desired product. r 

2. A compound according To claim 1 which is 3-(methylthio)chromone.
 3. A compound according to claim 1 which is 3(methylsulfinyl)chromone.
 4. A compound according to claim 1 which is 3(methylsulfonyl)chromone.
 5. A method for the preparation of the compound of claim 1 where X is non-existant which comprises treating a compound of the formula: 